Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene.
Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene.
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DOI：
10.1016/j.bbagrm.2015.08.004
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Tsuji Y
中科院分区：
文献类型：
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作者：
Ray PD;Huang BW;Tsuji Y
抗氧化基因血红素加氧酶-1（HO-1）的表达主要通过NFE 2相关因子2（Nrf 2）介导的抗氧化反应元件（ARE）的激活来诱导。基因转录受转录因子在增强子元件上的活性和表观遗传学改变如组蛋白的翻译后修饰的协同调节。然而，组蛋白修饰在Nrf 2-ARE轴中的作用在很大程度上仍然是未知的。环境污染物亚砷酸盐是HO-1表达和组蛋白H3丝氨酸10（H3 S10）磷酸化的有效诱导剂;因此，我们研究了Nrf 2和H3 S10磷酸化在亚砷酸盐诱导的ARE依赖性人HO-1基因转录激活中的关系。亚砷酸盐在人HaCaT角质形成细胞中增加了H3 S10整体磷酸化和HO-1启动子磷酸化，同时增加了HO-1转录。相反，亚砷酸盐诱导的H3 S10磷酸化和HO-1表达被N-乙酰半胱氨酸（NAC），c-Jun N-末端激酶（JNK）抑制剂SP 600125和JNK敲低（siJNK）阻断。有趣的是，通过SP 600125或siJNK消融亚砷酸盐诱导的H3 S10磷酸化，尽管抑制HO-1表达，但并不抑制Nrf 2核积聚或ARE结合。响应亚砷酸盐，Nrf 2与HO-1 ARE的结合先于HO-1 ARE处H3 S10的磷酸化。此外，亚砷酸盐介导的H3 S10在HO-1 ARE上的磷酸化占据率在Nrf 2缺陷的小鼠胚胎成纤维细胞中降低。这些结果表明Nrf 2-ARE轴中H3 S10磷酸化的参与，提出Nrf 2可能会影响HO-1 ARE和其他启动子区域的H3 S10磷酸化。我们的数据突出了砷激活的HO-1转录中Nrf 2和H3 S10磷酸化之间的复杂相互作用。
Expression of the antioxidant gene heme oxygenase-1 (HO-1) is primarily induced through NFE2-related factor 2 (Nrf2)-mediated activation of the antioxidant response element (ARE). Gene transcription is coordinately regulated by transcription factor activity at enhancer elements and epigenetic alterations such as the posttranslational modification of histone proteins. However, the role of histone modifications in the Nrf2-ARE axis remains largely uncharacterized. The environmental contaminant arsenite is a potent inducer of both HO-1 expression and phosphorylation of histone H3 serine 10 (H3S10); therefore, we investigated the relationships between Nrf2 and H3S10 phosphorylation in arsenite-induced, ARE-dependent, transcriptional activation of the human HO-1 gene. Arsenite increased phosphorylation of H3S10 both globally and at the HO-1 promoter concomitantly with HO-1 transcription in human HaCaT keratinocytes. Conversely, arsenite-induced H3S10 phosphorylation and HO-1 expression was blocked by N-acetylcysteine (NAC), the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and JNK knockdown (siJNK). Interestingly, ablation of arsenite-induced H3S10 phosphorylation by SP600125 or siJNK did not inhibit Nrf2 nuclear accumulation nor ARE binding, despite inhibiting HO-1 expression. In response to arsenite, binding of Nrf2 to the HO-1 ARE preceded phosphorylation of H3S10 at the HO-1 ARE. Furthermore, arsenite-mediated occupancy of phosphorylated H3S10 at the HO-1 ARE was decreased in Nrf2-deficient mouse embryonic fibroblasts. These results suggest the involvement of H3S10 phosphorylation in the Nrf2-ARE axis by proposing that Nrf2 may influence H3S10 phosphorylation at the HO-1 ARE and additional promoter regions. Our data highlights the complex interplay between Nrf2 and H3S10 phosphorylation in arsenite-activated HO-1 transcription.